Controlled release and taste masking oral pharmaceutical composition

ABSTRACT

Controlled release and taste masking compositions containing one or more active principles inglobated in a three-component matrix structure, i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally inglobated or dispersed in hydrophilic matrices. The use of a plurality of systems for the control of the dissolution of the active ingredient modulates the dissolution rate of the active ingredient in aqueous and/or biological fluids, thereby controlling the release kinetics in the gastrointestinal tract.

The present invention relates to controlled release and taste-maskingcompositions containing mesalamine (5-aminosalicylic acid) incorporatedin a three-component matrix structure, i.e. a structure formed bysuccessive amphiphilic, lipophilic or inert matrices and finallyincorporated or dispersed in hydrophilic matrices. The use of aplurality of systems for the control of the dissolution of the activeingredient modulates the dissolution rate of the active ingredient inaqueous and/or biological fluids, thereby controlling the releasekinetics in the gastrointestinal tract, and it also allows the oraladministration of active principles having unfavourable tastecharacteristics or irritating action on the mucosae of theadministration site, particularly in the buccal area. The compositionsare suitable to the oral administration or for acting topically at someareas of the gastrointestinal tract.

TECHNOLOGICAL BACKGROUND

The preparation of a sustained, controlled, delayed or anyhow modifiedrelease form can be carried out according to different knowntechniques: 1. The use of inert matrices, in which the main component ofthe matrix structure opposes some resistance to the penetration of thesolvent due to the poor affinity towards aqueous fluids; such propertybeing known as lipophilia. 2. The use of hydrophilic matrices, in whichthe main component of the matrix structure opposes high resistance tothe progress of the solvent, in that the presence of stronglyhydrophilic groups in its chains, mainly branched, remarkably increasesviscosity inside the hydrated layer 3. The use of bioerodible matrices,which are capable of being degraded by the enzymes of some biologicalcompartment. All the procedures listed above suffer, however, fromdrawbacks and imperfections.

Inert matrices, for example, generally entail nonlinear, butesponential, release of the active ingredient.

Hydrophilic matrices have a linear behaviour until a certain fraction ofactive ingredient has been released, then they significantly deviatefrom linear release.

Bioerodible matrices are ideal to carry out the socalled “site-release”,but they involve the problem of finding the suitable enzyme or reactiveto degradation.

Furthermore, they frequently release in situ metabolites that are notwholly toxicologically inert. A number of formulations based on inertlipophilic matrices have been described: Drug Dev. Ind. Pharm. 13 (6),1001-1022, (1987) discloses a process making use of varying amounts ofcolloidal silica as a porization element for a lipophilic inert matrixin which the active ingredient is incorporated.

The same notion of canalization of an inert matrix is described in U.S.Pat. No. 4,608,248 in which a small amount of a hydrophilic polymer ismixed with the substances forming an inert matrix, in a non sequentialcompenetration of different matrix materials.

EP 375,063 discloses a technique for the preparation of multiparticulategranules for the controlled-release of the active ingredient whichcomprises co-dissolution of polymers or suitable substances to form ainert matrix with the active ingredient and the subsequent deposition ofsaid solution on an inert carrier which acts as the core of the device.Alternatively, the inert carrier is kneaded with the solution containingthe inert polymer and the active ingredient, then the organic solventused for the their dissolution is evaporated off to obtain a solidresidue.

The resulting structure is a “reservoir”, i.e. is not macroscopicallyhomogeneous along all the symmetry axis of the final form.

The same “reservoir” structure is also described in Chem. Pharm. Bull.46 (3), 531-533, (1998) which improves the application through anannealing technique of the inert polymer layer which is deposited on thesurface of the pellets. To the “reservoir” structure also belong theproducts obtained according to the technique described in WO 93/00889which discloses a process for the preparation of pellets in hydrophilicmatrix which comprises: —dissolution of the active ingredient withgastro resistant hydrophilic polymers in organic solvents; —drying ofsaid suspension; —subsequent kneading and formulation of the pellets ina hydrophilic or lipophilic matrix without distinction of effectivenessbetween the two types of application.

EP 0 453 001 discloses a multiparticulate with “reservoir” structureinserted in a hydrophilic matrix. The basic multiparticulate utilizestwo coating membranes to decrease the release rate of the activeingredient, a pH-dependent membrane with the purpose of gastricprotection and a pH-independent methacrylic membrane with the purpose ofslowing down the penetration of the aqueous fluid. WO 95/16451 disclosesa composition only formed by a hydrophilic matrix coated with agastro-resistant film for controlling the dissolution rate of the activeingredient. When preparing sustained-, controlled-release dosage formsof a medicament topically active in the gastrointestinal tract, it isimportant to ensure a controlled release from the first phases followingadministration, i.e. when the inert matrices have the maximum releaserate inside the logarithmic phase, namely the higher deviation fromlinear release.

Said object has been attained according to the present invention,through the combination of an amphiphilic matrix inside an inert matrix,the latter formulated with a lipophilic polymer in a superficialhydrophilic matrix. The compositions of the invention are characterizedby the absence of a first phase in which the medicament superficiallypresent on the matrix is quickly solubilized, and by the fact theamphiphilic layer compensate the lack of affinity of the aqueous solventwith the lipophilic compounds forming the inner inert matrix.

DISCLOSURE OF THE INVENTION

The invention provides controlled release and taste masking oralpharmaceutical compositions containing mesalamine, comprising:

-   -   a) a matrix consisting of lipophilic compounds with melting        point lower than 90 C and optionally by amphiphilic compounds in        which the active ingredient is at least partially incorporated;    -   b) optionally an amphiphilic matrix;    -   c) an outer hydrophilic matrix in which the lipophilic matrix        and the optional amphiphilic matrix are dispersed;    -   d) optionally other excipients.

A particular aspect of the invention consists of controlled release oralcompositions containing mesalamine, comprising:

-   a) a matrix consisting of amphiphilic compounds and lipophilic    compounds with melting point below 90 C in which the active    ingredient is at least partially incorporated;-   b) an outer hydrophilic matrix in which the lipophilic/amphiphilic    matrix is dispersed;-   c) optional other excipients.

A further aspect of the invention provides taste masking oralpharmaceutical compositions containing mesalamine, comprising:

-   -   an inert or lipophilic matrix consisting of C6 C20 alcohols or        C8-C20 fatty acids or esters of fatty acids with glycerol or        sorbitol or other polyalcohols with carbon atom chain not higher        than six;    -   an amphiphilic matrix consisting of polar lipids of type I or II        or glycols partially etherified with C1-C4 alkyl chains;    -   an outer hydrophilic matrix containing the above matrices,        mainly formed by saccharide, dextrin, polyalcohol or cellulose        compounds or by hydrogels;    -   optional excipients to give stability to the pharmaceutical        formulation.

DETAILED DISCLOSURE OF THE INVENTION

The compositions of the invention can be prepared by a method comprisingthe following steps:

-   a) the active ingredient is first inglobated by simple kneading or    mixing in a matrix or coating consisting of compounds having    amphiphilic properties, which will be further specified below. The    active principle (s) can be mixed with the amphiphilic compounds    without the aid of solvents or with small amounts of water-alcoholic    solvents.-   b) The matrix obtained in a) is incorporated in a low melting    lipophilic excipient or mixture of excipients, while heating to    soften and/or melt the excipient itself, which thereby incorporates    the active ingredient by simple dispersion. After cooling at room    temperature an inert matrix forms, which can be reduced in size to    obtain inert matrix granules containing the active ingredient    particles.-   c) The inert matrix granules are subsequently mixed together with    one or more hydrophilic water-swellable excipients. The mixture is    then subjected to compression or tabletting. This way, when the    tablet is contacted with biological fluids, a high viscosity swollen    layer is formed, which coordinates the solvent molecules and acts as    a barrier to penetration of the aqueous fluid itself inside the new    structure. Said barrier antagonizes the starting “burst effect”    caused by the dissolution of the medicament inglobated inside the    inert matrix, which is in its turn inside the hydrophilic matrix.

The amphiphilic compounds which can be used according to the inventioncomprise polar lipids of type I or II (lecithin, phosphatidylcholine,phosphatidylethanolamine), ceramides, glycol alkyl ethers such asdiethylene glycol monomethyl ether(Transcutol (R)).

The lipophilic matrix consists of substances selected from unsaturatedor hydrogenated alcohols or fatty acids, salts, esters or amidesthereof, fatty acids mono-, di- or triglycerides, the polyethoxylatedderivatives thereof, waxes, ceramides, cholesterol derivatives ormixtures thereof having melting point within the range of 40 to 90 C,preferably from 60 to 70 C.

If desired, a fatty acid calcium salt may be incorporated in thelipophilic matrix which is subsequently dispersed in a hydrophilicmatrix prepared with alginic acid, thus remarkably increasing thehydrophilic matrix viscosity following penetration of the solvent frontuntil contact with the lipophilic matrix granules dispersed inside.

According to an embodiment of the invention, an amphiphilic matrix withhigh content in active ingredient, typically from 5 to 95% w/w, is firstprepared by dispersing the active ingredient or the mixture of activeingredients in a mixture of amphiphilic compounds, such as lecithin,other type II polar lipids, surfactants, or in diethylene glycolmonoethyl ether; the resulting amphiphilic matrix is then mixed orkneaded, usually while hot, with lipophilic compounds suitable to forman inert matrix, such as saturated or unsaturated fatty acids, such aspalmitic, stearic, myristic, lauric, laurylic, or oleic acids ormixtures thereof with other fatty acids with shorter chain, or salts oralcohols or derivatives of the cited fatty acids, such as mono-, di-, ortriglycerides or esters with polyethylene glycols, alone or incombination with waxes, ceramides, cholesterol derivatives or otherapolar lipids in various ratios so that the melting or softening pointsof the lipophilic compounds mixtures is within the range of 40 to 90 C,preferably from 60 to 70 C. Alternatively, the order of formation of theinert and amphiphilic matrices can be reversed, incorporating the inertmatrix inside the amphiphilic compounds.

The resulting inert lipophilic matrix is reduced into granules by anextrusion and/or granulation process, or any other known processes whichretain the homogeneous dispersion and matrix structure of the startingmixture.

The hydrophilic matrix consists of excipients known as hydrogels, i.e.substances which when passing from the dry state to the hydrated one,undergo the so-called “molecular relaxation”, namely a remarkableincrease in mass and weight following the coordination of a large numberof water molecules by the polar groups present in the polymeric chainsof the excipients themselves.

Examples of hydrogels which can be used according to the invention arecompounds selected from acrylic or methacrylic acid polymers orcopolymers, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkylcelluloses, polysaccharides, dextrins, pectins, starches andderivatives, natural or synthetic gums, alginic acid.

In case of taste-masking formulations, the use of polyalcohols such asxylitol, maltitol and mannitol as hydrophilic compounds can also beadvantageous.

The lipophilic matrix granules containing the active ingredient aremixed with the hydrophilic compounds cited above in a weight ratiotypically ranging from 100:0.5 to 100:50 (lipophilic matrix:hydrophilicmatrix). Part of the active ingredient can optionally be mixed withhydrophilic substances to provide compositions in which the activeingredient is dispersed both in the lipophilic and the hydrophilicmatrix, said compositions being preferably in the form of tablets,capsules and/or minitablets.

The compression of the mixture of lipophilic and/or amphiphilic matrix,hydrogel-forming compound and, optionally, active ingredient notinglobated in the lipophilic matrix, yields a macroscopicallyhomogeneous structure in all its volume, namely a matrix containing adispersion of the lipophilic granules in a hydrophilic matrix. A similarresult can also be obtained by coating the lipophilic matrix granuleswith a hydrophilic polymer coating.

The tablets obtainable according to the invention can optionally besubjected to known coating processes with a gastro-resistant film,consisting of, for example, methacrylic acids polymers(Eudragit (R)) orcellulose derivatives, such as cellulose acetophthalate.

The compositions of the invention can further contain conventionalexcipients, for example bioadhesive excipients such as chitosans,polyacrylamides, natural or synthetic gums, acrylic acid polymers.

The compositions of the invention can contain more than one activeingredient, each of them being optionally contained in the hydrophilicmatrix or in the inert amphiphilic matrix, and are preferably in theform of tablets, capsules or minitablets.

In terms of dissolution characteristics, contact with water or aqueousfluids causes the immediate penetration of water inside the moresuperficial layer of the matrix which, thanks to the presence of theaqueous solvent, swells due to the distension of the polymeric chains ofthe hydrogels, giving rise to a high viscosity hydrated front whichprevents the further penetration of the solvent itself linearly slowingdown the dissolution process to a well determined point which can belocated at about half the thickness, until the further penetration ofwater would cause the disintegration of the hydrophilic layer andtherefore the release of the content which, consisting of inert matrixgranules, however induces the diffusion mechanism typical of thesestructures and therefore further slows down the dissolution profile ofthe active ingredient.

The presence of the amphiphilic matrix inside the lipophilic matrixinert allows to prevent any unevenness of the release profile of theactive ingredient. The surfactants present in the amphiphilic portionpromote wettability of the porous canaliculuses which cross the inertmatrix preventing or reducing resistance to penetration of the solventinside the inert matrix.

To obtain taste masking tablets, the components of the hydrophilicmatrix are carefully selected to minimize the active substance releasetime through penetration accelerated by the canalization induced by thehydrophilic compound.

The following Example illustrate the invention in greater detail.

EXAMPLE 1

500 g of 5-aminosalicylic acid and 20 g of octylonium bromide are mixedwith 10 g of soy lecithin dissolved in 50 g of a water:ethyl alcohol 1:3mixture at about 50 C.

After homogenization and drying, the granules of the resulting matrixare treated in a kneader with 20 g of carnauba wax and 50 g of stearicacid, heating until homogeneous dispersion, then cold-extruded intosmall granules. The inert matrix granules are loaded into a mixer inwhich 30 g of carbopol 971 P and 65 g of hydroxypropyl methylcelluloseare sequentially added. After a first mixing step for homogeneouslydispersing the powders, 60 g of microcrystalline cellulose and 5 g ofmagnesium stearate are added. After mixing, the final mixture istabletted to unitary weight of 760 mg/tablet. The resulting tablets arefilm-coated with cellulose acetophthalate or polymethacrylates and aplasticizer to provide gastric resistance and prevent the early releaseof product in the stomach.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 60 minutes no more than 30%, after 180 minutesno more than 60%, after 5 hours no more than 80%.

1. Controlled release and taste-masking oral pharmaceutical compositionsin form of a tablet containing mesalamine as the active ingredient,comprising: a) a matrix consisting of lipophilic compounds with meltingpoint lower than 90° C. in which the active ingredient is at leastpartially dispersed, said lipophilic compounds being selected fromsaturated or unsaturated fatty acids in combination with waxes; b) anhydrophilic matrix in which the lipophilic matrix is dispersed, saidhydrophilic matrix consisting of carboxyalkylcellulose; and c)optionally a matrix consisting of amphiphilic compounds being selectedfrom polar lipids of type I, polar lipids of type II or glycolspartially etherified with C1-C4 alkyl chains in which the activeingredient is at least partially dispersed; which is then furtherdispersed in the hydrophilic matrix
 2. Compositions as claimed in claim1, wherein the saturated fatty acid is selected from palmitic, stearic,myristic, lauric, laurilic or oleic acids, or mixtures thereof. 3.Compositions as claimed in claim 1, wherein the saturated fatty acid isstearic acid.
 4. Compositions as claimed in claim 1, comprisingexcipients.
 5. Compositions as claimed in claim 1, comprising agastro-resistant coating.
 6. Compositions as claimed in claim 1, whereinthe gastro-resistant coating consists of methacrylic acid polymers orcopolymers or cellulose derivatives.
 7. Compositions as claimed in claim6, wherein the gastro-resistant coating contains a plasticizer.